Method of Using Silicon Substituted Phosphates to Improve Healing of Bone and Soft Tissue

ABSTRACT

A method of use of silicon substituted phosphates that improves bone and soft tissue growth resulting in better adhesion and fixation of implanted prosthetics, which may be used as part of a tissue engineering scaffold for ligament replacement and results in improved healing of healing of damaged bone and soft tissue ulcers. The silicon substituted phosphates of various chemical composition and granular sizes may be used in direct application or in combination with other materials, not previously claimed in prior art used to treat the various medical conditions described.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/490,579, filed Jun. 26, 2009, which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

The present invention relates to the use of inorganic chemicals classedas silicon substituted phosphates (SSPs), and more specifically to amethod for using silicon substituted phosphate formulations to improvebone and soft tissue growth, resulting in better adhesion and fixationof implanted prosthetics, which may be used as part of a tissueengineering scaffold for ligament replacement, and results in improvedhealing of damaged bone and soft tissue ulcers.

BACKGROUND OF THE INVENTION

When implanting prostheses such as total hip replacements, total kneereplacements, and total shoulder replacements, surgeons commonly usebone cement, such as methyl-methacrylate, to fix the prosthetic boneinserts into the bone. Complications associated with implantation ofprostheses include loosening and dislocation of the prosthetic which canresult in pain and/or bone breakage and require revision surgery. Onecause of loosening is inadequate prosthetic fixation to host tissue.Another cause of loosening is related to wear at the contact surface andthe prosthetic which releases particulates creating a granulation layerat the interface of the host tissue and contact surface. Additionally,the granulation layer imposes an inability to fully transfer mechanicalloads from bone to prostheses implanted with methyl-methacrylate bonecement. The mechanical failure of the granulation layer to fullytransmit load from bone to prosthesis and the inflammation fromparticulates increase the risk potential for loosening. Another cause ofloosening that has been observed when using bone cement is inadequatesoft tissue to bone attachment as well as to metal resulting inparticulates migrating in the granulation layer causing prostheticloosening.

Another situation in which soft tissue to bone attachment is importantis when tendons and/or ligaments must be replaced or reattached to boneafter injury. In these cases, a scaffold is used to afford a mechanicalstructure and protection during the time dependent chemical delivery ofthe multiple factors necessary for cellular growth and differentiation,ultimately leading to the matured replacement structure being capable offunctioning as engineered.

A situation in which soft tissue generation is important is in the caseof ulcerous wounds. Health conditions and/or injury can cause decreasedcirculation in the extremities and even a small wound can result in anulcer that is very difficult to heal.

Many formulations of silicon substituted phosphates (SSP) have beendeveloped to eliminate bone cement for use in dental applications (see,e.g., Hench, U.S. Pat. No. 5,981,412). As a result, various formulationsof SSP are commercially available and have been approved for use by theU.S. Food and Drug Administration. Dental implants have used SSPformulations in fixing dental prostheses that are implanted in thecontaminated, high load alveolar ridge. SSP application is known to fixthe prosthesis by promoting bone in-growth into the porous coatedprosthesis and directing bonding bone to the prosthesis. In addition tothe high bioactivity, the SSP formulations have shown no tendency toform fibrous tissue which would cause loosening.

The use of SSP implants in orthopedics has been limited because the SSPformulations that are known for promoting bone growth are mechanicallyweak with low fracture resistance. The bending strength is in the rangewhich is insufficient for load bearing application. Thus the orthopedicuse of SSP implants has been limited to non-load bearing applications orfor buried implants loaded slightly or compressively.

Thus, what is sought is a method for using an SSP formulation forpromoting bone and tissue growth in orthopedic applications whichinvolve load bearing bones or ulcerous skin conditions which overcomesone or more of the shortcomings and limitations, set forth above.

SUMMARY OF THE INVENTION

What is disclosed is a method for using a silicon substituted phosphate(SSP) formulation for promoting bone and tissue growth in orthopedicapplications which involve load bearing bones or ulcerous skinconditions which overcomes one or more of the shortcomings andlimitations, set forth above.

According to an aspect of the invention, an SSP formulation is used tofix medical devices, such as, but not limited to prosthetic implants, bypromoting direct soft tissue or bone adherence or in-growth to theprosthetic surface without intermediate tissue, such as granulationtissue, being formed.

According to a feature of the invention, the SSP formulation is used toachieve regeneration of tissue of the type to which it is contact. Thatis to say, for example, that when the SSP is in contact with muscle,muscle regenerates; when the SSP is in contact with skin, skinregenerates; when the SSP is in contact with vascular structures,vessels regenerate.

According to another aspect of the invention, because of theregenerative potentiation and anti-microbial characteristics the SSPformulation is used to treat diabetic and decubitus ulcers, traumaticinjuries, such as motor vehicle accident injuries, and the like.

According to yet another aspect of the invention, the SSP formulationmay be incorporated into various bioabsorbable fixation devices, suchas, but not limited to plates, screws, anchors, staples, interferencescrews, rods, and the like, of various compositions, such as, but notlimited to polylactic acid, polyglycolic acid, polyhydroxyalkonates,poliglecaprone, collagen preparations, and the like, to allow suchdevices to remodel into the host tissue type without the formation ofgranulation tissue and loosening.

According to another feature of the invention, application of the SSPformulation to bone soft tissue interfaces promotes the formation ofSharpey's fibers providing anatomic soft tissue to bone, loadtransferring bonds.

According to another feature of the invention, application of the SSPformulation to fractures with a high incidence of non or delayed unionprevents non or delayed union. Again, the SSP formulation may be used inconjunction with other compatible vehicles or carriers for ease ofapplication or injection, such as, but not limited to variousbiocompatible fluids or gels of various composition.

According to another feature of the invention, application of the SSPformulation to debrided bone cysts and benign bone tumors promotes thehealing of the created defects with normal bone.

According to yet another aspect of the invention, the application of theSSP formulation as a paste composed of aqueous thrombin and precipitatedcollagen to a bleeding bone controls the bleeding and promotes normalbone healing.

Additional advantages of the invention include a commercially available,FDA approved supply of the SSP formulation which is easily handled andused in a sterile environment, such as an operating room requiring onlyapplication to involved areas, with or without the use of specialapparatus. In addition, when used externally, the SSP formulation may beused by the patient to treat wounds or ulcers based on a doctor'sinstructions.

DETAILED DESCRIPTION OF THE INVENTION

A commercially available silicon substituted phosphate (SSP) is marketedunder the name Bioglas®, and in the studies described herein, the SSPdesignated 45S5 was used. The 45S5 name signifies an SSP with 45% SiO₂and a 5 to 1 ratio of CaO to P₂O₅. Lower ratios of CaO to P₂O₅ have notpromoted bonding with bone. More specifically the formulation by weightpercent (wt %) of 45S5 is shown in (1).

45S5 45 SiO₂, 6 P₂O₅, 24.5 CaO, and 24.5 Na₂O  (1)

A first study was performed which included 157 consecutive porous coatedtotal hip and knee prostheses implanted using the SSP formulationdesignated 45S5 and without using methyl-methacrylate bone cement.

According to the method of the present invention, the bioactive SSP wassprinkled on all of the porous coated surfaces of the prosthetic devicewhich had been wetted by normal saline/antibiotic solution. AdditionalSSP particles were mixed with autologous cancellous bone, and packed inall soft trabecular bone spaces, and in the sites adjacent to where theporous surfaces would be in contact. For larger defects additionalautologous or bank cancellous bone was mixed with additional materialand packed in the defects.

Retrospectively, 23 patients at high risk for loosening weresequentially selected for review without exclusion beginning withimplants in place the longest. All high risk implants reviewed wereimplanted for a minimum of 7 years. None of the high risk patients orthe remaining sequentially reviewed patients have had X-ray or clinicalevidence of loosening. None of the patients experienced infectionsduring the healing process. Bone pain was graded at 1 in 5, or less, inall patients, and in no instance did pain prevent activity or interferewith sleep. At grafted sites, X-rays confirmed new bone formationwithout resorbtion. At stem or “peg” ends the crescent shaped boneformation indicative of prosthetic micro-motion was usually absent, orif present, minimal. No radiolucency was noted adjacent to the surfacescoated with the material. In addition all soft tissue to bone attachmentusing the SSP modifying the growth and differentiation factor sequencewere successful.

Because the SSP effectively seals all bone and soft tissue interfacesbetween bone and metal prosthetic components, partially by promotingionic surface modification on metal, and enhancing soft tissue adhesion,no particulate loosening has been observed.

The anti-microbial character of the material discussed above, makes itideally suited for orthopaedic implant use. It has been observed thatsilicon inhibits the glycoprotein “slime” formation of staph epidermis.Research studying SSP activity suggests that the silicon contentby-passes the resorbtive or breakdown phase of inflammation thuspromoting early new bone formation and imparts an anti-microbialactivity. The tumor necrosis factor (TNF-α) and IL-1 are down-regulatedand the vascular endothelial growth factor (VEGF) is up-regulated in thecellular growth and differentiation factor cascade.

Bone stimulation and early bone deposition also make the material wellsuited for other high risk patients with bone metabolic compromise, suchas osteoporosis.

In another study a synthetic scaffold including the SSP designated 45S5as shown in (1) seeded with autologous mesenchymal stem cells fromadjacent or involved bone were implanted to replace a damaged anteriorcruciate ligament (ACL), without failure in any cases of 23 cases.Various implant procedures for ACLs, were utilized, but all procedureshad a tibial tunnel as the site of the mesenchymal stem celldevelopment. The femoral attachment was accomplished through either afemoral tunnel or an “over-the-top” configuration, with soft tissuefixation (one tunnel). The former terminated in either soft tissuefixation; over a bone bridge; used an absorbable or non-absorbableinterference screw, or a combination thereof. Arthroscopic orarthroscopically assisted, minimally open procedures were used forisolated ACL replacements. In some multi-trauma instances, theintra-articular ligament[s] (the ACL and/or PCL), and/or extra-articularligament[s] (the MCL and/or the LCL) were replaced, also without failurein volunteers. The post-operative rehabilitation was minimally limitingdue to the strength of the implant, but must be guarded to allow thein-growth tissue to mature in response to its environment.

In another study of approximately 15 patients presenting with fractureswith a high incidence of non or delayed union. Application of the SSPformulation at the fracture was successful in healing the fracturewithout non or delayed union characteristics.

In another study of approximately 30 patients having debrided bone cystsand/or benign bone tumors were treated with a mixture of autologouscancellous bone and the SSP formulation designated in (1). Healing ofthe bone defects to normal bone was successful in all of the patients.

In another study involving more than 250 volunteers, the SSP formulationwas used externally to promote tissue growth in ulcers or wounds thatwere difficult to heal because of inadequate blood flow to the area. TheSSP formulation designated 45SP as seen in (1) was applied daily aftercleaning the ulcerous area. The wound was covered loosely and kept dry.In all cases the participants reported that the ulcer or wound healingwas improved when compared to treatment methods used for previousulcers.

Because of the effectiveness of SSPs in anchoring prosthetic implants,the prevention of granulation particulates, the anti-microbial activity,the reconstituting soft tissue to bone interfaces, and its negligibleproduction cost, SSP formulations, such as 45S5 may be used in mostprosthetic implant procedures and soft tissue to bone repairs,particularly in high risk patients.

It is important to note that in most of the studies, the SSP formulationis applied internally typically by a doctor in an operating room. Oncethe incision is closed, the SSP formulation is remains inside thepatient. When treating wounds or ulcerous tissue, the SSP formulation isapplied externally, often by the patient. This use of the SSP isparticularly advantageous because it can be offered “over the counter”directly to patients. It allows the patient to apply the SSP to treatthe external ulcer according to a doctor's orders, most likely withouthospitalization and even possibly without visiting a doctor.

According to a feature of the invention, the SSP may sprinkled orotherwise directly applied to involved areas or other components oftreating modalities, such as but not limited to wound sites,prosthetics, tissue interfaces, debrided benign bone cysts and tumors,and the like.

According to another feature of the invention, the SSP formulation maybe used in combination with a vehicle or carrier to facilitate thepresentment of the invention to various sites, in some instances to lessaccessible areas, for example, by injection.

According to yet another feature of the inventions, the SSP formulationmay be combined in various proportions with other materials tofacilitate remodeling of various bioabsorbable devices.

The SSP used in the method of the invention is a sterile, dry compositewhich may be applied directly to open or accessible sites or may beotherwise deposited in a sol-gel derived material.

Because of the effectiveness of 45S5 SSP formulation in anchoringprosthetic implants, the prevention of granulation tissue,anti-microbial activity, reconstituting soft tissue to bone interfaces,and its availability, SSP formulations may be used in most prostheticimplant procedures and soft tissue to bone repairs. In addition the 45S5SSP formulation may be used to promote soft tissue growth in ulcerouswounds that are otherwise difficult to heal because of diminished bloodflow.

Advantages of the method of use of SSP formulations to improve healingof bone and soft tissue include use of an FDA approved substance that iscommercially available. Use of the SSP collectively provides a sterile,surgically implantable material for the regeneration of living tissuesof various composition, to allow tissue fixation to dissimilar tissueand other materials, to treat various medical conditions, and to promoteclotting. This material chemically modulates various cellular growth anddifferentiation factors such as, but not exclusive to tumor necrosisfactor, to promote tissue regeneration of the anatomic type that it isplaced in contact with, while exhibiting antimicrobial activity.

In light of all the foregoing, it should thus be apparent to thoseskilled in the art that there has been shown and described a method ofuse of SSP to improve healing of bone and soft tissue. However, itshould also be apparent that, within the principles and scope of theinvention, many changes are possible and contemplated, including in thedetails, materials, and arrangements of parts which have been describedto explain the nature of the invention. Thus, while the foregoingdescription and discussion addresses certain preferred embodiments orelements of the invention, it should further be understood that conceptsof the invention, as based upon the foregoing description anddiscussion, may be readily incorporated into or employed in otherembodiments and constructions without departing from the scope of theinvention. Accordingly, the following claims are intended to protect theinvention broadly as well as in the specific form shown, and allchanges, modifications, variations, and other uses and applicationswhich do not depart from the spirit and scope of the invention aredeemed to be covered by the invention, which is limited only by theclaims which follow.

What is claimed is:
 1. A method to promote healing of an ulcer having adepressed surface due to tissue erosion bound by a perimeter using asilicon substituted phosphate formulation, the method comprising:removing necrotic tissue from the depressed surface exposing reddenedtissue; cleansing the surface with a sterile solution; sprinkling alayer having a thickness of approximately 200 to 500 micrometers ofsilicon substituted phosphate granules on the reddened tissue such thatsubstantially all of the redness is masked by the layer; and coveringthe surface with a sterile bandage; wherein the silicon substitutedphosphate formulation comprises a composition by molecular weight ofapproximately 40 to 50 percent SiO₂, approximately 2 to 8 percent P₂O₅,approximately 20 to 30 percent CaO, and the remaining molecular weightapproximately 15 to 20 percent Na₂O, such that the ratio of CaO to P₂O₅is greater than or equal to 5 to
 1. 2. The method of claim 1, whereinthe silicon substituted phosphate formulation promotes healing of theulcer by encouraging regeneration of soft tissue.
 3. The method of claim1, wherein the silicon substituted phosphate formulation modifiescellular growth and differentiation factors and promotes secretion ofextracellular matrix and biochemical factors to regulate genes of a hosttissue to promote tissue regeneration of appropriate anatomic tissuewhen applied.
 4. The method of claim 1, wherein the silicon substitutedphosphate formulation exhibits anti-microbial activity while promotingsoft tissue regeneration.
 5. The method of claim 1, wherein the siliconsubstituted phosphate formulation is a sol-gel derived material and isdeposited in a thin layer on the reddened tissue such that substantiallyall of the redness is masked by the thin layer.
 6. The method of claim1, wherein the silicon substituted phosphate formulation is directlyapplied to the ulcer surface or admixed with a vehicle or carrier forapplication to the ulcer surface.